THE CHARACTER OF INHIBITION OF THE METABOLISM OF 1,2-BENZOPYRONE (COUMARIN) BY GRAPEFRUIT JUICE IN HUMAN

Objective: Constituents of grapefruit juice are known to interfere wit h mammalian cytochrome P450 isozymes such as intestinal CYP3A4 and hep atic CYP2A6, lowering the biotransformation of drugs and increasing th eir bioavailability. The aim of this study was to investigate whether the presence of naringin is demanded for the inhibition of the coumari n 7-hydroxylase in man or other compounds are responsible for it. Meth ods: In cross-over studies, doses of 10 mg coumarin, together with com binations of grapefruit juice, water and naringin, were given orally t o one healthy male volunteer. We investigated increasing amounts of gr apefruit juice, keeping the volume of liquid constant at 1 L; increasi ng doses of naringin given in water; increasing amounts of juice, keep ing the dose of naringin constant; or increasing doses of naringin, ke eping the amount of juice constant. Urine samples were collected up to 24 h after dosing and 7-hydroxycoumarin was quantified fluorimetrical ly in urine hydrolysates after HPLC separation to determine the excret ion rates. Results: While increasing amounts of grapefruit juice delay the excretion of 7-hydroxycoumarin by 2 h, increasing doses of naring in in water up to twofold (i.e. naringin content of 2 L grapefruit jui ce) do not cause any alteration in the time course of excretion. Exper iments with increasing amounts of juice, keeping the dose of naringin constant, indicate that the inhibitory potency of small amounts of gra pefruit juice can be amplified by naringin. The same is true when the ratio between juice constituents and naringin is enhanced up to threef old by adding naringin. Conclusion: As naringin alone is ineffective, the inhibitory effect of grapefruit juice on the metabolism of coumari n is caused by at least one compound other than naringin. The persiste ncy of the primary inhibitor-not identified yet can obviously be modul ated by the naring(en)in-system.